Cardiovascular disease is the major cause of morbidity and mortality in our society. The broad category of cardiovascular disease refers to obstructive vascular disease and includes coronary artery disease, cerebral vascular insufficiency (stroke), peripheral vascular insufficiency and deep vein thrombosis. Although the precise pathogenesis of these diseases is unknown, each of these disorders is associated with activation of the blood clotting system and subsequent deposition of fibrin (clot) in the vascular space. This deposition either initiates or aggravates vascular obstruction and insufficiency. Thus the treatment of these diseases frequently involves some agent to interfere with blood coagulation.
Attempts to interact therapeutically with the blood clotting system focus on either increasing blood clot dissolution by the firbinolytic system or prevention of blood clot (fibrin) formation by an anticoagulant. The former approach has gained recent popularity with the production of specific fibrinolytic (plasminogen) activators by gene cloning technology. This includes production of tissue plasminogen activator, a potentially important fibrinolytic agent. These agents will actively dissolve preformed clots in the vascular space and thus will be used in acute vascular obstruction, e.g. acute myocardial infarction. Ths disadvantages of these agents are that they are applicable only in the acute phase of obstructive vascular disease and that they must be administered parenterally under close medical supervision.
Inhibition of blood coagulation for therapeutic purposes is currently attempted by one of two approaches: either the blood concentrations of certain clotting factors are lowered by vitamin-K antagonists such as warfarin, or the natural anticoagulant potential, namely antithrombin III heparin cofactor activity of the blood is increased by heparin. Recently, another approach involving specific synthetic or natural product inhibitors of the clotting proteases has been investigated. These inhibitors interact either reversibly or irreversibly with thrombin or other coagulation proteases to produce an anticoagulant effect.
Each of the anticoagulant agents which are currently in use or under investigation has advantages and disadvantages. Vitamin-K antagonists are orally effective and long acting but have a slow onset of action which is not easily reversed. There are also many problematic drug interactions which may be unrecognized by the clinician. Heparin, heparinoids and hirudin are rapid acting and very effective. Heparin is also easily reversed with protamine. However these agents are difficult to isolate and are only effective parentally due to their high molecular size and complex polysaccharide or polypeptide structure. The synthetic low molecular weight inhibitors appear to be effective orally and rapid acting. However, their effects are of short duration and may not be specific to the clotting proteases. Furthermore, the production costs of these synthetic compounds may be high.
Clearly there is room for improvement in the field of anticoagulants useful to treat those in need of such treatment.